This application is for renewed funding for years 6-10 of R01 AI48793. Our long-term objective isto determine the genetic mechanisms influencing the immune response to live viral vaccines, and to answer the question of how and to what degree differences in immune responses that depend upon the immunogenetics of the individual determine the outcome of immunization with live viral vaccines. Because of the central role of cytokines as intercellular protein messengers, and their receptors, in the immune response cascade, the role of cytokine and cytokine receptor gene polymorphisms will be a primary focus of this application, and we will focus on the influence of these polymorphisms on measures of humoral and cellular immune response to a live viral vaccine - rubella - asa model with which to explore the influenceof immunogenetics on the variability of vaccine response. To accomplish these goals, we propose thefollowing specific aims: 1) To test_the hypothesis that significant associations exist between polymorphisms of specific cytokine genes (IFNa, (3, y, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12A, IL-12B, TNFa and GM-CSF) and rubella immune responses (neutralizing antibody level and markers of cell-mediated immunity), 2) To test the hypothesis that significant associations exist between polymorphisms of specific cytokine receptor genes (IL-2RA, IL-2RB, IL-2RG, IL-4R, IL-6R, IL-6ST, IL-10RA, IL-10RB, IL-12RB1, IL-12RB2, IFNAR1, IFNAR2, IFNGR1, IFNGR2, TNFRSF1A, TNFRSF1B, CSF2RA and CSF2RB), and rubella immune responses, 3) To test the hypothesis that significant associations exist between secreted cytokine protein levels (IFNa, (3, y, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p35 and p40), TNFa and GM-CSF) after ex vivo rubella stimulation and rubella immune responses, and 4) To verify the associations between class I and II HLA genes and rubella immune responses found in our previous study and to assess potential effects of gene-gene interactions on these immune responses within a new validation cohort. The proposal is innovative as it examines the effect of immunogenetics on variability of vaccine response. The significance of this information is that it will provide a framework for estimating the contribution of HLA variability on variability of immune responses as well as provide knowledge important to the development of new viral vaccines (HIV, HPV, Hepatitis C, and others) in a genetically heterogeneous population. Relevance to Public Health: This grant proposes to study the genes that influence and determine the human immune response to rubella vaccine. The knowledge gained from these studies will enable us to design new strategies and new vaccines to protect human health against viral diseases.